Verapamil (1, below) is presently in clinical use as the racemate and is used extensively for the treatment of hypertension. The (S)-enantiomer (levoverapamil) has the majority of the calcium channel antagonist activity (see DE-A-2059923), whilst the (R)-enantiomer (dextroverapamil) differs in having sodium channel and other cell-pump actions in addition to higher bioavailability, with slower clearance rate. Therefore, single isomer products may have clinical utility. For example, the (R)-enantiomer may be of benefit for the treatment of multidrug resistance in cancer chemotherapy (see Eliason, Int. J. Cancer (1990) 46: 113). ##STR1##
There is, therefore, a requirement for efficient processes to manufacture enantiomerically-enriched forms of verapamil and its analogues. This is a challenging endeavour since construction of the quaternary chiral centre with high asymmetric induction is difficult. Several synthetic routes have been published, but for a variety of reasons these are not suitable for operation on a large scale.
For example, Theodore and Nelson, J. Org. Chem. (1987) 52:1309, describe a synthesis of (S)-verapamil commencing from (S)-1,2-propanediol which entails eleven steps, only three of which are used to create permanent skeletal bonds. Of the shorter routes proceeding via classical resolution, a process reported in WO-A-9509150, involving resolution of the secondary amine intermediate and subsequent conversion to single enantiomer verapamil, is advantageous over resolution or verapamil itself, which is described in DE-A-3723684 and WO-A-9316035, due to better atom utilisation and lower waste levels.
Alternatively, resolution of a racemic acid precursor would appear to provide an attractive route. Indeed, resolution of 4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoic acid (verapamilic acid 2, below) has already been reported in DE-A-2059923 using brucine, together with elaboration to enantiomerically-enriched verapamil. However, there is doubt as to whether this resolution process is reproducible. In addition, brucine is highly toxic, and thus unsuitable for a large-scale manufacturing process. ##STR2##